Although extensive research has been conducted with children who have sickle cell disease, there is a paucity of studies on adults with the disease. Many adult patients with sickle cell disease (SCD) experience daily pain. Although the pathophysiology of sickle cell related pain is complex, microcirculatory occlusion with tissue ischemia and activation of inflammatory cascades are believed to be involved. Acute vasoocclusive crises are responsible for most sickle cell related medical visits. Despite strong evidence for a role of tissue and vascular inflammation in the initiation and maintenance of acute vasoocclusive crises, no specific serum biomarkers have been identified which correlate with the intensity or duration of the acute crisis. An effective mode of analgesic treatment that can be assessed by serum biomarker and improved has not been methodically investigated in SCD pain crisis. Therefore, the objective of this R21 proposal is to test the hypothesis that quality and method of analgesia affect the level of specific blood biomarkers and can be correlated with pain levels. Thus, this study would provide a unique opportunity to understand the treatment effects of sickle cell crisis on pain and provide a basis for future interventions and clinical use of specific serum biomarkers. The first aim is to test the hypothesis that the mode of analgesia technique affects the outcome of pain crisis as determined by pain scores, analgesic consumption and hospital admission rates in SCD pain crisis. The SCD subjects will be enrolled during a regular hospital visit (total target of 75 subjects) and followed up during the emergency visit for the acute pain crisis. The standard analgesic technique of parenteral and oral opiate treatment will used. The aim is to assess the effect of analgesic treatment on acute and subacute pain levels during and after an acute sickle pain crisis and to identify serum inflammatory/pain molecules as biomarkers for pain severity in SCD pain crisis and to test the hypothesis that serum biomarkers can be used to predict need for admission, increased need for analgesics, and possibly disease complication rates in SCD. Furthermore, to determine if the analgesic treatment influence serum biomarkers and can be used as a predictor of analgesic efficacy. The baseline levels of plasma IL-12, TNF-1, Substance P (SP), heat shock protein 70 (HSP70), nitrite levels (measure of nitric oxide synthase activity) and agmatine will be determined in all enrolled subjects during the regular hospital visit. The levels of these plasma markers will be measured during the emergency visit for acute pain crisis and before discharge. The final analysis of the biomarkers will be made during the scheduled visit at 2 to 4 weeks after the acute pain crisis. At the conclusion, this study will produce two basic sets of preliminary data both of which will allow a more in-depth evaluation of the mechanisms of SCD pain syndrome and other treatment options. PUBLIC HEALTH RELEVANCE: One of the objectives of this R21 program announcement is to develop translational research program where laboratory-based scientific discoveries are applied into practical/clinical settings in pain conditions. Accordingly, the objective of this Proposal is to evaluate the standard analgesic treatment option during sickle cell disease (SCD) pain crisis and to identify serum biomarkers that will predict the occurrences and for treatment outcome during pain crisis. Thus, this Proposal is well under the scope of the PA-06-542 as an exploratory proposal in attempting to understand the efficacy of analgesic treatment and whether novel serum biomarkers can be identified as useful tools for future studies in SCD pain crisis.